Functional STAT3 deficiency compromises the generation of human T follicular helper cells
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Date
2012-04-26
Authors
Ma, Cindy S.
Avery, Danielle T.
Chan, Anna
Batten, Marcel
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
Arkwright, Peter D.
Kreins, Alexandra Y.
Averbuch, Diana
Engelhard, Dan
Journal Title
Journal ISSN
Volume Title
Publisher
The American Society of Hematology
Abstract
T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12R beta 1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
Description
Keywords
Hematology, Cxc chemokine receptor-5, Tyrosine phosphorylation, Antibody-responses, Th17 cells, Mutations, Differentiation, Mycobacterial, Il-21, Icos, Bcl6
Citation
Ma, C. S. vd. (2012). "Functional STAT3 deficiency compromises the generation of human T follicular helper cells". Blood, 119(17), 3997-4008.